Flagellin engineering enhances CAR-T cell function by reshaping tumor microenvironment in solid tumors.

Area of Science:

• Immunology
• Cancer Therapy
• Cellular Engineering

Background:

• Adoptive cell therapy with chimeric antigen receptor (CAR)-T cells shows promise for hematologic malignancies.
• The immunosuppressive tumor microenvironment (TME) limits CAR-T cell efficacy in solid tumors.
• Strategies to remodel the TME are crucial for enhancing CAR-T cell therapy in solid tumors.

Purpose of the Study:

• To engineer CAR-T cells to express Salmonella flagellin (Fla) to activate immune cells and remodel the TME.
• To evaluate the therapeutic potential of Fla-engineered CAR-T cells in solid tumors.

Main Methods:

• CAR-T cells were engineered to express Salmonella flagellin (Fla).
• Functional validation was performed in co-cultures and mouse tumor models.

Main Results:

• Fla-engineered CAR-T cells activated tumor-associated macrophages and dendritic cells, converting the TME to an "immune-hot" milieu.
• This immune modulation enhanced CAR-T cell function and improved control of target-positive solid tumors.
• Fla expression also promoted endogenous cytotoxic CD8+ T cell production, enhancing efficacy against tumors with antigenic heterogeneity.

Conclusions:

• Salmonella flagellin (Fla) can rewire antitumor immunity by remodeling the TME.
• Engineering CAR-T cells to express Fla is a viable strategy to improve therapeutic efficacy against solid tumors.